DESCRIPTION Ischemic pain occurs when tissue gets insufficient oxygen for its metabolic demand. Clinical examples include angina, intermittent claudication, and the intense pain accompanying sickle-cell anemia. Prior and current work from the McCleskey laboratory suggests that an acid-sensing ion channel, ASICS (also called DRASIC), may be a primary transducer of ischemic pain. Using genetically-altered mice, I hope to determine the role of this channel in ischemia-related muscle nociception. I have developed a new in vitro muscle-nerve preparation, which I will use in conjunction with patch clamp analysis of ion currents to examine ASICS current in response to specific ischemia-related stimuli. Most importantly, the new muscle-nerve preparation will allow me to determine whether ASICS responses are relevant in a physiological context. If successful, several important questions and paradoxes concerning ischemic pain will finally be answered. In addition, the experiments described in this proposal may validate a pharmaceutical target for the treatment of ischemic pain.